Dataset Information

Friedreich’s ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis

ABSTRACT: Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disease caused by a guanine-adenine-adenine (GAA) trinucleotide repeat expansion within the first intron of the FXN gene. The GAA expansion in FRDA induces a transcriptionally repressive state that reduces expression of the protein product Frataxin. Despite Frataxin's ubiquitous expression, the dorsal root ganglia sensory neurons (SNs) are particularly affected, causing sensory/proprioceptive loss, while lower motor neurons (LMNs) are largely spared in FA. The basis for this cell-type specific selective vulnerability remains a central unanswered question in FRDA pathophysiology. Here we generated induced pluripotent stem cell derived sensory neurons, lower motor neurons and neural crest cells from FRDA and isogenic corrected control cell lines. These were profiled using bulk RNA sequencing and used in the systematic review and meta-analysis of all human bulk RNA-seq datasets derived from FRDA and control samples. Our group performed a systematic review and meta-analysis of human bulk RNA-sequencing datasets in FRDA, reprocessing all studies through a unified analysis pipeline to enable direct cross-study comparison. We analysed 23 independent datasets comprising 94 FRDA and 99 control samples across 10 distinct cell types, spanning both disease-relevant (cardiomyocytes, sensory neurons) and unaffected cell types (fibroblasts, lymphocytes) of FRDA. This integrative approach allowed us to identify transcriptional changes that are consistently associated with FRDA across studies, while simultaneously delineating those that are cell-type specific. We have identified a panel of robust biomarkers of FRDA that would be useful readouts in in vitro drug screens, in clinical trials, as well as generating hypothesis as to how these biomarkers relate to the pathophysiological mechanisms of FRDA. All biomarkers, datasets and results can also be explored through the open-access FRDA Transcriptomic Atlas (https://marniemaddock.github.io/FRDATranscriptomicAtlas/).

ORGANISM(S): Homo sapiens

PROVIDER: GSE319887 | GEO | 2026/03/18

REPOSITORIES: GEO

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Dataset's files

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			Action	DRS
		Other
	GSE319887_Maddock_gene_counts.csv.gz	Csv
	GSE319887_Maddock_gene_tpm.csv.gz	Csv
	GSE319887_Maddock_transcript_counts.csv.gz	Csv
	GSE319887_Maddock_transcript_tpm.csv.gz	Csv

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Project description:Friedreich ataxia (FRDA) is a multisystemic, autosomal recessive disorder caused by a homozygous GAA expansion mutation in the first intron of frataxin (FXN) gene. FXN is a mitochondrial protein critical for iron-sulfur cluster biosynthesis and deficiency impairs mitochondrial electron transport chain functions and iron homeostasis within the organelle. Currently, there is no effective treatment for FRDA. We have previously demonstrated that a single infusion of wild-type hematopoietic stem and progenitor cells (HSPCs) resulted in the prevention of the neurologic and cardiac complications of FRDA in YG8R mice, and the rescue was mediated by FXN transfer from tissue engrafted HSPC-derived microglia/macrophages to diseased neurons/myocytes. For a future clinical translation of this approach, we developed an autologous stem cell transplantation approach using CRISPR/Cas9 for the excision of the GAA repeats in FRDA patients’ CD34+ HSPCs; this strategy leading to increased FXN expression and improved mitochondrial functions in the cells. The aim of the current study is to validate the efficiency and safety of our gene editing approach in a disease-relevant model. To this end, we generated a cohort of FRDA patient-derived iPSCs and isogenic lines that were gene edited with our CRISPR/Cas9 approach. FRDA neurons generated from these iPSCs displayed characteristic apoptotic and mitochondrial phenotype of the disease, such as non-homogenous microtubule staining in neurites, increased caspase-3 expression, mitochondrial superoxide levels, mitochondrial fragmentation, and partial degradation of the cristae compared to healthy controls. These defects were fully prevented in the gene edited neurons. RNASeq analysis of FRDA and gene edited neurons demonstrated striking improvement in gene clusters associated with endoplasmic reticulum (ER) stress in the isogenic lines. These results were validated by molecular and functional studies, and gene edited neurons demonstrated improved ER-calcium release, normalization of ER stress response gene, XBP-1, and significantly increased ER-mitochondrial contacts that are critical for functional homeostasis of both organelles, as compared to FRDA neurons. Ultrastructural analysis for these contact sites displayed severe structural damage to the ER in FRDA neurons, that was undetected in gene edited neurons. Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage and function in FRDA. In addition, these results validate the efficacy profile of our FXN gene editing approach, in a disease relevant model improving mitochondrial and cellular, and supporting our approach as an effective strategy for therapeutic intervention for Friedreich’s ataxia.

Project description:Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in FRDA patients. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three FRDA patients, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Together, these findings establish a robust human iPSC model of FRDA cardiomyopathy that captures early disease phenotypes and reveals novel molecular targets. This preclinical human model provides valuable insight into the pathogenesis of FRDA and provides a platform for developing early-stage therapeutic interventions.

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Friedreich’s ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis

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